tbuckley/cabot-search huggingface dataset:
<i>ATM</i> or <i>CHEK2</i> alterations: Potential biomarkers of improved outcomes with irinotecan-containing chemotherapy in advanced pancreatic ductal adenocarcinoma.
Authors: Maahum Mehdi, Bicky Thapa, Aniko Szabo, Gulrayz Ahmed, Aditya V. Shreenivas, James P. Thomas, Deepika Sriram, Douglas B. Evans, Susan Tsai, Kathleen K. Christians, Beth Erickson, William A. Hall, Thomas McFall, Steve Patrick, Ben George, Razelle Kurzrock, Mandana Kamgar
Journal: Journal of Clinical Oncology (2023)

754 Background: ATM and CHEK2 mutations are linked to homologous recombination DNA repair deficiency, with the potential for improved therapeutic response to DNA damaging agents. To investigate our clinical observation of improved outcomes with irinotecan (IRI) based chemotherapy in advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) with somatic or germline ATM/ CHEK2 mutations, we examined our institutional real world experience. Methods: Between 2015-2021, 33 pts with ATM or CHEK2 mutations treated with chemotherapy were identified, of which 16 pts had advanced/metastatic disease. Progression-free survival (PFS) was calculated and compared (Kaplan Meier, log-rank test) in several ways to assess the impact of IRI vs platinum or other regimens. The event for PFS was progression (or death), and pts without progression were censored at treatment end, or at last follow up if treatment was ongoing. Results: Among 16 pts with advanced/metastatic PDAC, 8 (50%) had ATM (5 germline, 3 somatic) and 8 (50%), CHEK2 alterations (4 germline, 4 somatic). Overall, pts received 48 lines of chemotherapy (platinum-based-(No-IRI) N=14; IRI-based-(No-Platinum) N=8; both N=4; none N=22). For best-PFS among pts analysis, median line of best-PFS therapy for IRI-Ever (N=9 pts) was 2 nd line (range 1-7) and for IRI-Never (N=7 pts) was 1st (range, 1-1); median PFS was 13 vs 3 months (mo) (IRI-Ever vs IRI-Never; p=0.0076). For PFS analysis within lines of treatment of each pt, median therapy line for both IRI-containing and No-IRI lines was 2 nd line (range 1-7); median PFS for IRI-containing (N=12 lines of therapy) vs No-IRI (N=36) was 12.1 vs 3 mo (p&lt;0.001). Median PFS for best IRI-based-(No-Platinum) line (N=7) was 13 mo; for best platinum-based-(No-IRI) line (N=9) was 2.8 mo; and for best treatment containing no IRI or platinum (N=13) was 5.1 mo (P= 0.003) (median therapy line for each was 3, 2 and 1.5, respectively). Conclusions: Irinotecan is a topoisomerase 1 inhibitor that induces DNA strand breaks, potentially causing synthetic lethality in tumors with DNA damage repair deficits due to ATM or CHEK2 alterations. IRI-containing therapy out-performed other treatment types, including platinum-containing regimens, in pts with ATM or CHEK2-mutated advanced/metastatic PDAC. Prospective trials are warranted.
The relationship between CT-derived sarcopenia, systemic inflammation, physical function and survival in patients with advanced cancer.
Authors: Josh McGovern, Ross D Dolan, Claribel Simmons, Barry Laird, Marie T. Fallon, Derek Gerard Power, Louise Daly, Aoife M Ryan, Paul G. Horgan, Donald C. McMillan
Journal: Journal of Clinical Oncology (2023)

804 Background: The CT-derived sarcopenia score (CT-SS) is thought to capture the nutritional and functional reserve of the cancer patient. However, it is unknown whether the CT-SS is associated with measures of physical function in patients with advanced cancer. Furthermore, has complimentary prognostic value when utilised as a phenotypic criterion in the GLIM cachexia framework. Methods: Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011–2016, was retrospectively analysed. Relationships between the CT-SS, ECOG-PS, measures of physical function and aetiological GLIM criterion (mGPS and metastatic disease) were examined using χ 2 test for linear-by-linear association. Results: 518 patients met the inclusion criteria. 55 % (n=286) were male and 51% (n=266) were 65 years of age. The majority of patients had either GI (47%, n=242) or lung (25%, n=129) tumours. 46% (n=241) were CT-SS ≥1. 53% (n=274) of patients were inflamed (mGPS≥1). 63% (n=325) had an ECOG-PS&gt;0/1. Of the 192 patients who underwent timed up-and-go testing and two-minute walk testing, 72% (n=138) and 96% (n=185) were categorised as a failure, respectively. Median survival from entry to the study was 8.7 months (4.2-18.3). 84% (n=433), 64% (n=339) and 38% (n=194) of patients were alive at 3-, 6- and 12-months, respectively. The CT-SS was significantly associated with ECOG-PS (p&lt;0.001), timed up-and-go test failure (p&lt;0.05), two-minute walk test failure (p&lt;0.05), 3-month survival (p&lt;0.05), 6-month survival (p&lt;0.05) and 12-month survival (p&lt;0.05). Furthermore, was significantly associated with 3-, 6- and 12-month survival in patients who were mGPS 0 and did not have metastatic disease (p&lt;0.05 and p&lt;0.05, respectively). Conclusions: The CT-SS is associated with physical function and survival in patients with advanced cancer. Furthermore, has complementary prognostic value to the aetiological criterion of the GLIM framework.
nextHERIZON: A phase 2 study of HER-Vaxx, a HER2-targeting peptide vaccine, in combination with chemotherapy or pembrolizumab in patients with HER2 metastatic or advanced gastric/gastroesophageal adenocarcinoma that progressed on or after trastuzumab treatment.
Authors: Timothy Jay Price, Leslie Mi Ok Chong, Nicholas Ede, Bonnie Nixon, Nimali Withana, Sharon Yavrom, Giovanni Selvaggi, Anthony J. Good
Journal: Journal of Clinical Oncology (2023)

TPS481 Background: HER-Vaxx is a B-cell peptide vaccine composed of a fusion of 3 epitopes from the extracellular domain of HER2/neu conjugated to CRM197 with the adjuvant Montanide. Results from a phase 1b study revealed that active immunization with HER-Vaxx was well tolerated and induced HER2-dose dependent immune responses corresponding to tumor reduction in advanced gastric cancer (GC) or gastroesophageal adenocarcinoma (GEA) (Wiedermann, 2021). A phase 2 study, HERIZON, comparing HER-Vaxx plus standard chemotherapy or chemotherapy alone is currently enrolling. Pre-clinical data demonstrated a synergistic effect with combination of HER2 and PD-1 vaccines and 90% tumor growth inhibition (Kaumaya, 2020). Ramucirumab plus paclitaxel is an approved second-line treatment for patients with GC or GEA who have failed first-line treatment chemotherapy or trastuzumab (TRA) (Wilke, 2014). The nextHERIZON study seeks to evaluate the clinical benefit of adding HER-Vaxx to ramucirumab plus paclitaxel or pembrolizumab, following progression on TRA. Methods: nextHERIZON is phase 2, open-label, non-comparative, double arm, 2-stage design study in patients with confirmed AGC and HER2 overexpression following progression on or after TRA. Arm assignment depends on prior PD-1/PD-L1 inhibitor treatment. Arm 1 will receive HER-Vaxx + ramucirumab and paclitaxel. Arm 2 will receive HER-Vaxx + pembrolizumab. Up to 55 patients will be enrolled in each arm which includes a safety run-in phase. Arms will be analyzed independently. The key inclusion criteria are: patients ³ 18 year of age; ECOG 0 or 1; minimum life expectancy of 3 months; progressed on or after TRA; confirmed HER2 overexpression; at least one measurable lesion; adequate hematologic and organ function. Key exclusion criteria include previous treatment with trastuzumab-deruxtecan or any other anti-HER2 therapy other than trastuzumab. Arm 2 excludes prior therapy with anti- PD-1, PD-L1 or PD-L2 agents. The co-primary endpoints are safety and objective response rate (RECIST 1.1). Secondary objectives are efficacy and survival measures. HER-Vaxx is administered by intramuscular (IM) injection on Day 1, Day 15, and Day 29 and on Day 1 of each 2 nd or 3 rd cycle depending on arm. Dose-limiting toxicity (DLT) window is 29 days on treatment. Tumor assessment is evaluated at Day 43 then every 6 weeks until progression or withdrawal. This study is currently enrolling patients in Australia and US (Q1 2023). Clinical trial information: NCT05311176 .
A multicenter, single-arm, phase II study of nivolumab in patients with biliary tract cancer with a PD-L1 combined positive score ≥ 1.
Authors: Masayuki Furukawa, Makoto Ueno, Daisuke Sakai, Kota Ouchi, Yasuo Hamamoto, Hiroshi Aikata, Masato Ozaka, Hidetaka Tsumura, Kunihiro Tsuji, Shoji Kubo, Tomohiro Nishina, Akio Katanuma, Chigusa Morizane, Masafumi Ikeda, Nobumasa Mizuno, Takashi Inagaki, Kazuhiko Shioji, Junji Furuse
Journal: Journal of Clinical Oncology (2023)

533 Background: Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and high unmet medical needs still exist for the treatment of this disease. Nivolumab has shown its effectiveness against multiple cancer types, especially those with PD-L1 expression. This study assessed the efficacy and safety of nivolumab in BTC patients with a combined positive score (CPS) ≥ 1 who were refractory or intolerant to the standard of care (SOC): gemcitabine, cisplatin and tegafur/gimeracil/oteracil (S-1). Methods: This was a single-arm, multicenter, open-label, prospective phase II study. Key eligibility criteria were as follows: having unresectable or recurrent BTC (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer); being refractory or intolerant to SOC; having adequate hepatic, renal and hematological function; and having a CPS ≥ 1 in central assessment. Patients received nivolumab (480 mg, every 4 weeks) until disease progression, clinical deterioration, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the central review according to RECIST 1.1. The secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled between Mar 11, 2020 and Mar 15, 2021, of them 12 received one regimen and 72 received two or more regimens. The median follow-up period was 6.90 months. ORR per central assessment was 10.7% (CR: 3.6%, PR: 7.1%), and ORR per investigator assessment was 15.5% (CR: 2.4%, PR: 13.1%). The median PFS per central and investigator assessment was 1.02 (95% CI 0.95–1.77) months and 2.48 (95% CI 1.87–2.83) months, respectively. The median OS was 6.90 (95% CI 5.26–9.20) months. The median duration of response per central and investigator assessment was not reached (range 2.8–13.0+) and 10.15 (range 2.0–12.8+) months, respectively. The 1-year survival rate was 25.3% (95% CI 15.4–36.4). The most frequent treatment-related adverse events were pyrexia (19.0%), pruritus (16.7%), and decreased appetite (13.1%). Conclusions: Nivolumab may have some activity with a durable response and a manageable safety profile in heavily treated BTC patients with CPS ≥ 1. Clinical trial information: JapicCTI-205097 .
HCRN GI16-288: A phase II trial of perioperative CV301 vaccination in combination with nivolumab and systemic chemotherapy for resectable hepatic-limited metastatic colorectal cancer—Preliminary efficacy and correlative results.
Authors: Kristen Renee Spencer, Howard S. Hochster, Patrick M Boland, Lyudmyla Derby Berim, Timothy Kennedy, Miral Grandhi, Russell C Langan, Dirk F. Moore, Michael P. Kane, Smitha S. Krishnamurthi, Skye C. Mayo, Anup Kasi, Agustin Pimentel, Darren R. Carpizo
Journal: Journal of Clinical Oncology (2023)

103 Background: Novel strategies to improve the efficacy of immune checkpoint inhibitors in microsatellite stable (MSS) mCRC are needed. CV301 is a vector-based vaccine that expresses carcinoembryonic antigen (CEA) and mucin 1 (MUC1), and in a phase II study in resected hepatic limited mCRC significantly improved OS compared with unvaccinated contemporary controls. Methods: In this multi-center randomized phase II study, patients with previously untreated resectable hepatic-limited mCRC were randomized to perioperative nivolumab + mFOLFOX +/- CV301 (Arm B) with a primary endpoint of 3-year OS. Treatment included mFOLFOX-nivo (+/- CV) x 4 cycles followed by resection, then 8 more cycles of mFOLFOX-nivo followed by maintenance nivo monthly for two years in both arms, and CV boosters concurrently with mFOLFOX, and then every 3 months for two years in arm B. Secondary endpoints of ORR (following induction pre-resection), PRR, and safety were determined. Correlative analyses included immune cell quantification using Immunoscore and T-cell clonality. Results: 17 patients were enrolled prior to premature closure for slow accrual (8 arm A, 9 arm B). At the time of data cutoff, 5 patients remained on treatment and no deaths had occurred. One patient was removed from study due to protocol non-compliance. The median age was 61, majority were male (59% vs 41%), and ECOG PS 0-1 (71% 0, 17% 1). All patients had complete surgical resection. Four patients (24%) experienced a SAE related to drug. The TRAE rate was 40.3%,. No AEs delayed/prevented surgical resection. The ORR in arm A was 50% (including 4 CR) and 87.5% in arm B (including 7 CR) (p=0.129, NS). There was no significant difference in pathologic response (p=0.9047). Correlative analyses demonstrated the Immunoscore CD3/CD8 predicted response to mFOLFOX + nivolumab, but did not correlate with response to CV301, though CV301 may induce a shift to predominantly cytotoxic CD8+ T cells. While there was no significant difference in T cell repertoire, clonality, fraction (TCFr) or richness, patients in arm B had significant decreases in blood TCFr and increase in tumor TCFr with treatment; those with CR had higher TCFr and clonality. Conclusions: The addition of CV301 to perioperative nivolumab and mFOLFOX was safe, did not delay or prevent surgical resection, and gave a higher response (p=ns due to sample size). Changes in T cells suggest a vaccine response. Clinical trial information: NCT03547999 . [Table: see text]
Long-term quality of life in patients with metastatic esophagogastric cancer receiving first-line systemic therapy.
Authors: Marieke Pape, Pauline A.J. Vissers, Marije Slingerland, Nadia Haj Mohammad, Lonneke van de Poll-Franse, Rob Verhoeven, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2023)

306 Background: Thus far, evidence that quality of life (QoL) remains stable during 1 st line systemic therapy of patients with metastatic esophagogastric cancer (mEGC) originates from randomized clinical trials (RCTs). Outcomes from a population-based study provides inside into the effect of systemic therapy on HRQoL in daily clinical practice. The aim of this study was to assess QoL of patients with mEGC at baseline, during 1 st line, at progression and after disease progression. Methods: Patients diagnosed with mEGC (2014-2020) receiving 1 st line systemic therapy registered in the Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) were included. QoL was measured with the EORTC QLQ-C30 and -OG25 at baseline, during 1 st line therapy, at progression and after disease progression. Results: Of the 263 included patients, 123, questionnaires were available at baseline, 161 during 1 st line, 77 at progression and 89 after progression. Results of the mixed effect models showed that global health status and four functioning scales deteriorated after progression as compared to baseline. Largest improvements during 1 st line treatment were observed for odynophagia (mean change -17.3), anxiety (-14.9), dysphagia (-11.7) and eating restrictions (-11.1). Trouble with taste deteriorated at all three time points. Conclusions: In accordance to RCTs, QoL outcomes remained relatively stable or improved during 1 st line therapy in patients with esophagogastric cancer. Deterioration of functioning scales were mainly observed after progression. [Table: see text]
The oncologic implications of tumor multiplicity in intrahepatic cholangiocarcinoma: Its prognostic value might be underestimated.
Authors: So Jeong Yoon, Subin Oh, Hyun Jeong Jeon, Hye Jeong Jeong, Soo Yeun Lim, Sang Hyun Shin, Jin Seok Heo, In Woong Han
Journal: Journal of Clinical Oncology (2023)

611 Background: In the latest staging system of the American Joint Committee on Cancer (AJCC) for intrahepatic cholangiocarcinoma (IHCCC), solitary tumor with vascular invasion and multiple tumors are grouped together as T2. However, recent studies have reported that multifocal IHCCC have worse prognosis than a single lesion. This study aimed to investigate risk factors of IHCCC and to explore the prognostic significance of multiplicity identified by surgical resection. Methods: A total of 277 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival of resected IHCCC. Survival outcomes were compared between patients with solitary tumors and those with multiple tumors. Results: In multivariable analysis, presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were risk factors for survival. Among 82 patients with T2, overall survival was significantly better in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p = 0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. Stage II-sT2 group showed prolonged survival than those with stage II-mT2 or stage III. Survival of stage II-mT2 patients was not statistically different from that of stage III patients. Conclusions: Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and be reflected in the next update of staging system.[Table: see text]
Racial disparities in tumor microbiome in young-onset and average-onset colorectal cancer.
Authors: Heloni M Dave, Naseer Sangwan, Kanika G. Nair, Shimoli V Barot, David Liska, Stephanie Schmit, Alok A. Khorana
Journal: Journal of Clinical Oncology (2023)

13 Background: The occurrence of young-onset colorectal cancer (yoCRC) is rising alarmingly, with a disproportionate incidence in Black patients as compared to White. We and others have previously shown differences in tumor microbiomes between yoCRC and average-onset colorectal cancer (aoCRC), but it is unknown if these differences contribute to racial disparities. We therefore analyzed racial differences in the intra-tumoral microbiome of CRC in young adults (&lt;50 years). Methods: We analyzed 277 samples of histologically confirmed cases of stage I-IV CRC patients identified as either non-Hispanic Black or non-Hispanic White, who underwent surgical resection at Cleveland Clinic from year 2000-2020, who consented to a prospective biorepository. Fresh frozen specimens from the primary tumor with paired adjacent nonmalignant tissue were analyzed. The 16s rRNA gene was amplified and sequenced using V4 region primers and Illumina’s MiSeq system. Using DADA2, the quality filtered 16S rRNA amplicon reads were clustered and annotated as amplicon sequence variants (ASVs). The abundance count matrix was analyzed for alpha and beta diversity and differential abundance analysis (DAA) using Phyloseq package. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression and Wilcoxon test. DAA and correlation analysis were controlled for false discovery rate using Benjamini Hochberg correction. Results: Differential abundance analysis highlighted key differences in the microbiome composition of Black and White patients with yoCRC. Amongst Black patients, the most prevalent taxa were Limosilactobacillus, Bacillus, Staphylococcus, Listeria and Akkermansia, whereas amongst White patients the most prevalent taxa were Enterococcus and Escherichia-Shigella (Table). Microbial profiles were also significantly different between Black patients with yoCRC and aoCRC and between White patients with yoCRC and aoCRC. At ASV level, the microbiome of Black yoCRC is more similar (R2 =0.87) to Black aoCRC, in comparison to white yoCRC (R2=0.57). Conclusions: We found significant differences between the intra-tumoral microbiome of yoCRC in the United States by race. Future epidemiologic studies and public health interventions need to account for these differences to reduce risk of yoCRC across various US populations. [Table: see text]
The efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors: A multicenter, retrospective study.
Authors: Weili Yang, Haoran Qian, Litao Yang, Pengfei Wang, Hailong Qian, Binbin Chu, Zhuo Liu, Jingyu Sun, Dan Wu, Lifeng Sun, Wenqiang Zhou, Jingwei Hu, Xiaolei Chen, Chunhui Shou, Lingxiang Ruan, Jiren Yu
Journal: Journal of Clinical Oncology (2023)

800 Background: Ripretinib is a switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and platelet-derived growth factor receptor α (PDGFRA) kinase signaling. Ripretinib demonstrated favorable therapeutic efficacy and safety in clinical trial settings and was approved for advanced GIST who have received prior treatment with three or more TKIs. Here, we report the efficacy and safety of ripretinib in Chinese patients with advanced GIST in a multicenter, retrospective study. Methods: Patients with advanced GIST who received ripretinib in ZheJiang province were included and analyzed. The primary endpoint was progression-free survival (PFS) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 GIST-Specific Standard. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of therapy (DOT), safety and overall survival (OS). Exploratory endpoint was the predominant genotype for ripretinib treatment. Results: 23 patients were enrolled, while 21 patients were included in the study. The median number of prior lines of therapy was 3 (range, 0-4). The site of primary tumor was predominantly the small intestine (52.38%) and 47.62% of patients with ECOG performance status≥2. Median PFS was 7.1 months (95% CI, 4.9-NA), the ORR and DCR were 9.52% and 85.71%, respectively. Median duration of therapy was 7.3 months (range, 1.8-12). For patients on ≥fourth-line therapy, the median PFS was 9.2 months (95% CI, 4.6-NA), the ORR and DCR were 7.14% and 100%, respectively. Shorter interval between the end of the latest TKI and ripretinib therapy was correlated with longer median PFS and OS (P = 0.021 and P = 0.009, respectively). In univariate analysis, patients with KIT exon 9 mutation had a shorter PFS than patients without KIT exon 9 mutation (hazard ratio, 3.692; 95% CI, 1.109 to 12.294; P = 0.033). Patients with KIT exon 17/18 mutation had a longer PFS (hazard ratio, 0.097; 95% CI, 0.011 to 0.871; P = 0.037). Ripretinib was associated with a favorable safety profile, grade 3 treatment-emergent adverse events (TEAEs) were recorded in 5 patients. No grade 4 or 5 TEAEs were recorded. Conclusions: The ECOG performance status of the patients that received ripretinib in this study is poor. Ripretinib can provide clinical benefit in advanced GIST in real-world China with a favorable safety profile. Immediately switch from the latest TKI to ripretinib after progression will prolong the survival of the patients.